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  • 1
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In this study sequence-specific antisense oligonucleotide probes have been used to investigate the distribution of the mRNAs coding for the somatostatin receptor subtypes termed somatostatin receptor 1, somatostatin receptor 2 and somatostatin receptor 3 in the rat brain and pituitary using in situ hybridization techniques. The three receptor subtype mRNAs were found to be widely distributed in the brain with different patterns of expression, but with some overlap. Somatostatin receptor 1 mRNA was particularly concentrated in the cerebral and piriform cortex, magnocellular preoptic nucleus, hypothalamus, amygdala, hippocampus, and several nuclei of the brainstem. Somatostatin receptor 3 mRNA was very abundant in the cerebellum and pituitary (in contrast to somatostatin receptor 1), but it was also found in hippocampus, amygdala, hypothalamus and in motor nuclei of the brainstem. Somatostatin receptor 2 mRNA levels were very low relative to the other two mRNAs evaluated. Receptor 2 mRNA was observed in the anterior pituitary, and in the brain it was found in the medial habenular nucleus, claustrum, endopiriform nucleus, hippocampus, some amygdala nuclei, cerebral cortex and hypothalamus. None of the three somatostatin receptor mRNAs studied here was found in the caudate nucleus. Northern analysis revealed distinct sizes of mRNAs for each subtype, and displacement experiments showed that each probe sequence was subtype-specific.
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have used in vivo microdialysis in anaesthetised rats to investigate whether somatostatin (SRIF) can play a neuromodulatory role in the striatum. When 100 nM SRIF was retrodialysed for 15 min, it increased concentrations of dopamine (DA) by 28-fold, γ-aminobutyric acid (GABA) by eightfold, and glutamate (Glu) by sixfold as well as those of aspartate (Asp) and taurine (Tau). These effects were both calcium- and tetrodotoxin-sensitive. Lower (10 or 50 nM) and higher (1 µM) SRIF concentrations were less effective. Rapid sampling showed that whereas Asp and Glu concentrations were raised for 3 min at the start of 15-min SRIF infusions, those of DA were increased for 12 min. A second 15-min application of 100 nM SRIF given 135 min after the first application failed to increase transmitter release. An NMDA receptor antagonist, 2-amino-5-phosphonopentanoic acid (200 µM), blocked SRIF (100 nM)-evoked Asp, Glu, Tau, and GABA release and reduced that of DA. An α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (100 µM), blocked SRIF-induced DA and Tau release and reduced that of Asp, Glu, and GABA. These results show that SRIF increases DA, Glu, Asp, GABA, and Tau release in the rat striatum and suggest that its actions on DA and GABA release are mainly mediated through increased excitatory amino acid release.
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  • 3
    ISSN: 1432-1912
    Keywords: P2x Purinoceptors ; α,β-methylene ATP binding ; Rat vas deferens ; Rat spleen ; Rat cerebral cortex ; Rat heart ; Rat liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Radioligand binding studies have been performed to study the distribution of the binding sites for the P2x purinoceptor selective agonist radioligand, [3H]α,β-methylene ATP ([3H]αβ-meATP), in membranes prepared from various peripheral organs and several brain regions of the rat. In agreement with previous studies in the rat vas deferens, [3H]αβ-meATP labelled two populations of sites. One site exhibited high affinity for the ligand (Kd = 0.7 nM; Bmax = 1012 fmol.mg−1 protein) while the other site exhibited lower affinity (Kd = 70.8 nM) and higher capacity (Bmax = 7470 fmol. mg−1 protein). In competition studies, using a low concentration of radioligand (1 nM), the high affinity αβ-meATP binding sites in vas deferens membranes could be preferentially labelled (84–91%). Under these conditions, the PZx purinoceptor agonists, αβ-meATP and β,γ-methylene ATP, had the highest affinity with pIC50 values of 8.3 and 7.3 respectively. The P2y purinoceptor agonist, 2-methyl-thio-ATP (2-me-S-ATP), had lower affinity (pIC50 = 6.7), while uridine triphosphate, adenosine diphosphate and adenosine, agonists at the P2u, P2t and P1 purinoceptors, respectively, possessed low affinity (pIC50 values 〈 5.6). In addition, the P2 purinoceptor antagonists, cibacron blue and suramin, inhibited binding over the same concentration range at which they behave as functional antagonists at the P2x purinoceptor. High and low affinity binding sites for [3H]αβ-meATP were also identified in a range of other peripheral tissues (spleen, heart and liver) and in several brain regions (striatum, cerebral cortex, hippocampus). In the spleen, heart, cerebral cortex and liver the Kd values at both the high affinity binding sites (Kd = 1 – 1.2 nM) and the low affinity binding sites (Kd = 98 – 158 nM) were similar to the respective Kd values at the high and low affinity binding sites in the vas deferens. In competition studies performed using a low concentration of radioligand (1 nM) these sites exhibited a similar pharmacological profile to that seen in the vas deferens. Detailed analysis of competition curves to several of the ATP analogues in each of the tissues revealed that the binding profile of the radioligand was complex since several compounds, and in particular ATP and 2-meS-ATP, identified a lower proportion of sites with high affinity than did αβ-meATP The simplest interpretation of these data is that there are both high and low affinity sites for [3H]αβ-meATP in all tissues, but that the high affinity sites display heterogeneity with respect to various purinoceptor agonists. We conclude that this study demonstrates the presence of high affinity binding sites for [3H]αβ-meATP in a range of peripheral tissues and in several brain regions. These sites display a pharmacological profile which suggests that they reflect binding to a P2x purinoceptor. The apparent heterogeneity of these high affinity sites may be a consequence of agonist-induced conformational changes which we speculate may be linked with desensitisation states of the receptor.
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  • 4
    ISSN: 1432-1912
    Keywords: Px purinoceptors ; Calcium ; Magnesium ; Zinc ; Rat vas deferens ; α,β-methyleneATP binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study we have examined the effect of metal cations (as their chloride salts) on the binding of [3H]α,β-methylene ATP ([3H]αβmeATP) to rat vas deferens membranes using a vacuum filtration receptor binding assay. Whereas NaCl and KCl (0.01 and 30 mM) did not affect total binding of 1 nM [3H]αβmeATP, several divalent and trivalent cation salts markedly increased binding. The trivalent cation salts, FeCl3 and AlCl3 (0.1 to 100 μM), produced the greatest increases in total binding of [3H]αβmeATP, however, their effects were most probably due to precipitation of the radioligand. In contrast, several divalent cations, at concentrations between 1 μM and 1–10 mM, increased total binding of [3H]αβmeATP to rat vas deferens by between 87% and 215% while having no effect on either filter binding or non specific binding. The following pEC50 values for potentiating binding of the radioligand were obtained: ZnCl2 (5.44), MnCl2 (4.52), CaCl2 (4.17), CoCl2 (4.06), MgCl2 (3.67) and BaCl2 (3.10). Both EDTA and EGTA (0.01–1 mM) inhibited the binding of the radioligand. The effects of ZnCl2, CaCl2 and MgCl2 were examined in saturation studies. In the absence of added divalent cations, [3H]αβmeATP labelled both high (pKd = 9.15) and low (pKd = 7.06) affinity binding sites. The affinity of the radioligand for its high affinity sites was increased by 3 mM CaCl2 (pKd = 9.56) and by 30 μM ZnCl2 (pKd = 9.46) but not by 3 mM MgCl2. The Bmax of the low affinity site for [3H]αβmeATP was increased (approximately 4 fold) by both 3 mM MgCl2 and 30 μM ZnCl2 but not by 3 mM CaCl2. The selective effect of CaCl2 on the high affinity binding sites enabled these sites to be labelled in the presence of 3 mM CaCl2 using a low concentration of [3H]αβmeATP (1 nM); the sites exhibited the binding characteristics expected of the P2x purinoceptor. The selective effect of MgCl2 on the low affinity binding sites enabled these sites to be labelled in the presence of 3 mM MgCl2 and using a high concentration of [3H]αβmeATP (100 nM). A comparison of the binding characteristics of the high and low affinity sites for [3H]αβmeATP revealed several other differences, in addition to their cation selectivity. First, the adenine analogues ADP, αβmeATP and adenosine tetraphosphate possessed between 13 and 62 fold higher affinity for the high affinity [3H]αβmeATP binding sites than for the low affinity binding sites. Secondly, GTP-γ-S and pyrophosphate were selective ligands for the low affinity [3H]αβmeATP binding sites possessing approximately 43 and 1995 fold, respectively, higher pIC50 values at the low affinity sites than at the high affinity sites. Finally, treatment of the membranes with 0.01–1 mM N-ethyl maleimide increased low affinity binding of the radioligand while not affecting binding to the high affinity sites. The binding characteristics of the low affinity sites suggest that they do not equate with functional P2x purinoceptors; their identity remains to be determined. There was evidence for heterogeneity of both the high and low affinity sites for [3H]αβmeATP since competition curves to several nucleotide and polyphosphate compounds displayed Hill slopes less than unity. In conclusion the present study has demonstrated that cations have a marked effect on the binding of [3H]αβmeATP in rat vas deferens. Of particular interest was the ability of CaCl2 to increase the affinity of the radioligand for its high affinity sites enabling these sites to be selectively labelled, while the ability of MgCl2 to increase the Bmax of the low affinity binding sites enabled these sites to be selectively labelled.
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  • 5
    ISSN: 1432-1912
    Keywords: Key words P2X Purinoceptor ; βγ-Methylene-L-ATP ; Rat vagus nerve ; Nodose ganglion neurones ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effects of the putative selective P2X purinoceptor agonist, β,γ-methylene-L-adenosine 5′-triphosphate (βγme-L-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors. βγMe-L-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 μM. In contrast, the archetypal P2X purinoceptor agonist, α,β-methylene ATP (αβmeATP; 1–100 μM), produced concentration-related depolarisation responses with a mean EC50 value of 10.8 μM. The depolarising effects of αβmeATP were not attenuated by βγme-L-ATP (100 μM). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 μM), but not βγme-L-ATP (1–300 μM), evoked rapid (〈20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, βγme-D-ATP and αβmeATP competed with high affinity for [3H]αβmeATP binding sites, with mean pIC50 values of 7.7 and 8.3, respectively. However, βγme-L-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 μM (mean pIC50 value 4.1). In prostatic segments of the rat vas deferens, βγme-L-ATP (1–100 μM) and αβmeATP (0.3–100 μM) each produced concentration-related contractile responses with mean EC50 values of 17.1 and 3.6 μM, respectively. βγMe-L-ATP (1–10 μM) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [3H]αβmeATP exhibited high affinity for βγme-L-ATP, αβmeATP and βγme-D-ATP with mean pIC50 values of 7.7, 8.4 and 7.3, respectively. These results indicate that βγme-L-ATP exhibits neither agonist nor antagonist properties at P2X purinoceptors on rat vagal neurones and possesses only very low affinity for [3H]αβmeATP binding sites in rat brain. In contrast, βγme-L-ATP is a potent, high affinity agonist at smooth muscle P2X purinoceptors of the rat vas deferens. This selective agonist action of βγme-L-ATP suggests that P2X purinoceptors in smooth muscle and neurones are different and represent distinct P2X purinoceptor subtypes.
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  • 6
    ISSN: 1432-1912
    Keywords: P2X Purinoceptor ; βγ-Methylene-l-ATP ; Rat vagus nerve ; Nodose ganglion neurones ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the putative selective P2X purinoceptor agonist, β,γ-methylene-l-adenosine 5′-triphosphate (βγme-l-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors. βγMe-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 μM. In contrast, the archetypal P2X purinoceptor agonist, α, β methylene ATP (αβmeATP;1–100 μM), produced concentration-related depolarisation responses with a mean EC50 value of 10.8 μM. The depolarising effects of αβmeATP were not attenuated by βγme-l-ATP (100 μM). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 μM), but not βγme-l.-ATP (1–300 μM), evoked rapid ( 〈 20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, βγme-d-ATP and αβmeATP competed with high affinity for [3H]Lx βmeATP binding sites, with mean pIC50 values of 7.7 and 8.3, respectively. However, βγme-l-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 μM (mean pIC50 value 4.1). In prostatic segments of the rat vas deferens, βγme-l-ATP (1–100 μM) and αβmeATP (0.3–100 μM) each produced concentration-related contractile responses with mean EC50 values of 17.1 and 3.6 μM, respectively. βγMe-l-ATP (1–10 μM) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [3H]αβmeATP exhibited high affinity for ββ γme-l-ATP, αβmeATP and βγme-d-ATP with mean PIC50 values of 7.7, 8.4 and 7.3, respectively. These results indicate that βγme-l-ATP exhibits neither agonist nor antagonist properties at P2X purinoceptors on rat vagal neurones and possesses only very low affinity for [3H]αβmeATP binding sites in rat brain. In contrast, βγme-l-ATP is a potent, high affinity agonist at smooth muscle P2X purinoceptors of the rat vas deferens. This selective agonist action of βγme-l-ATP suggests that P2X purinoceptors in smooth muscle and neurones are different and represent distinct P2X purinoceptor subtypes.
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  • 7
    ISSN: 1432-1912
    Keywords: Somatostatin ; BIM-23027 ; Rat colonic mucosa ; sst2 receptors ; SRIF-binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously shown that the somatostatin (SRIF) sst2 receptor-selective peptide, BIM-23027, is a potent antisecretory agent in rat isolated distal colonic mucosa (RDCM) and in radioligand binding studies in RDCM membranes, it only maximally inhibited approximately 40% of [125I]-Tyr11-SRIF-14 binding (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg's Arch Pharmacol 352:402–411). The aim of this study was to characterise the BIM-23027-sensitive and -insensitive SRIF binding sites in more detail and to compare their properties with those of the recombinant sst2 receptor stably expressed in mouse fibroblast (Ltk−) cells. SRIF-14, SRIF-28, CGP-23996 and D Trp8-SRIF-14 abolished [125I]-Tyr11-SRIF-14 binding (pIC50 values, 8.7–9.7) but the competition curves had Hill slopes which were less than unity. Octreotide and L-362,855 inhibited binding over a wide concentration range (0.1 nM-1 μM) and inhibition of binding was incomplete at the highest concentration studied. BIM-23056 (PIC50 〈6.5) was a weak inhibitor of [125]-Tyr11-SRIF-14 binding. GTPγS decreased [125I]-Tyr11-SRIF-14 binding by 40%. Further binding experiments with [125I]-Tyr11-SRIF-14 were carried out in RDCM in the continuous presence of BIM-23027 (1 μM). Under these conditions, seglitide had no effect on [125I]-Tyr11-SRIF-14 binding at concentrations up to 10 μM, whilst SRIF-14 and SRIF-28 abolished specific [125I]-Tyr11-SRIF-14 binding in a manner which was consistent with the ligand binding to two sites. SRIF-14 and SRIF-28 displayed high affinity (pIC50 values of 9.8 and 9.3 respectively) for approximately 70% of these binding sites and low affinity (pIC50 values of 7.8 and 7.3) for the remaining sites. Octreotide, L-362,855 and BIM-23056 were weak inhibitors of [125I]-Tyr11-SRIF-14 binding (PIC50 〈6.5). [125I]-BIM-23027 labelled a single population of SRIF binding sites in RDCM membranes and mouse fibroblast (Ltk−) cells stably expressing the human recombinant sst2 receptor. There was a significant correlation between the affinitestimates of a range of SRIF analogues at inhibiting [125I]-BIM-23027 binding in RDCM membranes and binding to the recombinant sst2 receptor in Ltk− cells, suggesting that the sites labelled by [125I]-BIM-23027 in RDCM are similar to the sst2 receptor. GTPγS (100 μM) decreased [125I]-BIM-23027 binding in RDCM by 60%. The results from these studies demonstrate that [125I]-Tyr11-SRIF-14 labels a heterogeneous population of high affinity SRIF binding sites in RDCM membranes. The majority of these sites are insensitive to GTPγS and display negligible affinity for the cyclic hexapeptides, BIM-23027 and seglitide. The remaining high affinity binding sites can be selectively labelled with [125I]-BIM-23027, are sensitive to GTPγS and show similar characteristics to the recombinant sst2 receptor which appears to mediate the antisecretory effects of SRIF in the mucosa (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg's Arch Pharmacol 352:402–411).
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  • 8
    ISSN: 1432-1912
    Keywords: Key words Somatostatin ; BIM-23027 ; Rat colonic mucosa ; sst2 receptors ; SRIF-binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously shown that the somatostatin (SRIF) sst2 receptor-selective peptide, BIM-23027, is a potent antisecretory agent in rat isolated distal colonic mucosa (RDCM) and in radioligand binding studies in RDCM membranes, it only maximally inhibited approximately 40% of [125I]-Tyr11-SRIF-14 binding (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg‘s Arch Pharmacol 352:402–411). The aim of this study was to characterise the BIM-23027-sensitive and -insensitive SRIF binding sites in more detail and to compare their properties with those of the recombinant sst2 receptor stably expressed in mouse fibroblast (Ltk–) cells. SRIF-14, SRIF-28, CGP-23996 and D Trp8-SRIF-14 abolished [125I]-Tyr11-SRIF-14 binding (pIC50 values, 8.7–9.7) but the competition curves had Hill slopes which were less than unity. Octreotide and L-362,855 inhibited binding over a wide concentration range (0.1 nM-1 μM) and inhibition of binding was incomplete at the highest concentration studied. BIM-23056 (pIC50 〈6.5) was a weak inhibitor of [125]-Tyr11-SRIF-14 binding. GTPγS decreased [125I]-Tyr11-SRIF-14 binding by 40%. Further binding experiments with [125I]-Tyr11-SRIF-14 were carried out in RDCM in the continuous presence of BIM-23027 (1 μM). Under these conditions, seglitide had no effect on [125I]-Tyr11-SRIF-14 binding at concentrations up to 10 μM, whilst SRIF-14 and SRIF-28 abolished specific [125I]-Tyr11-SRIF-14 binding in a manner which was consistent with the ligand binding to two sites. SRIF-14 and SRIF-28 displayed high affinity (pIC50 values of 9.8 and 9.3 respectively) for approximately 70% of these binding sites and low affinity (pIC50 values of 7.8 and 7.3) for the remaining sites. Octreotide, L-362,855 and BIM-23056 were weak inhibitors of [125I]-Tyr11-SRIF-14 binding (pIC50 〈6.5). [125I]-BIM-23027 labelled a single population of SRIF binding sites in RDCM membranes and mouse fibroblast (Ltk–) cells stably expressing the human recombinant sst2 receptor. There was a significant correlation between the affinity estimates of a range of SRIF analogues at inhibiting [125I]-BIM-23027 binding in RDCM membranes and binding to the recombinant sst2 receptor in Ltk– cells, suggesting that the sites labelled by [125I]-BIM-23027 in RDCM are similar to the sst2 receptor. GTPγS (100 μM) decreased [125I]-BIM-23027 binding in RDCM by 60%. The results from these studies demonstrate that [125I]-Tyr11-SRIF-14 labels a heterogeneous population of high affinity SRIF binding sites in RDCM membranes. The majority of these sites are insensitive to GTPγS and display negligible affinity for the cyclic hexapeptides, BIM-23027 and seglitide. The remaining high affinity binding sites can be selectively labelled with [125I]-BIM-23027, are sensitive to GTPγS and show similar characteristics to the recombinant sst2 receptor which appears to mediate the antisecretory effects of SRIF in the mucosa (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg‘s Arch Pharmacol 352:402–411).
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  • 9
    ISSN: 1432-1912
    Keywords: Key words P2X7 receptor ; Cations ; Anions ; YO-PRO-1 ; Dibenzoyl-ATP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The actions of monovalent and divalent ions on the P2X7 receptor have been assessed by measuring their effect on responses to the P2 receptor agonist, 2’- and 3’-O-(4-benzoyl-benzoyl)-ATP (DbATP), in HEK293 cells expressing the human recombinant P2X7 receptor. In these cells, DbATP increased the cellular accumulation of the DNA binding, fluorescent dye, YO-PRO-1. The potency of DbATP to elicit this effect was decreased by both calcium and magnesium ions. In addition, when the pH was increased above 8 or reduced below 6.5, the potency of DbATP was less than obtained at pH 7.5. Monovalent ions also affected the P2X7 receptor such that the potency of DbATP was 19-fold higher in NaCl-free buffer containing 280 mM sucrose (pEC50=6.48) than in 140 mM NaCl containing buffer (pEC50=5.19). Monovalent cations differentially affected the potency of DbATP. Thus, when the chloride concentration was maintained at 140 mM, pEC50 values for DbATP were 6.14, 5.87 and 5.19 when the counter cation was 140 mM choline, potassium or sodium, respectively. Monovalent anions also differentially affected the potency of DbATP and in the presence of 140 mM sodium ions, pEC50 values for DbATP were 6.14, 6.07, 5.19 and 4.53, respectively, when the counter anion was 140 mM aspartate, glutamate, chloride or iodide. The inhibitory effect of monovalent anions on P2X7 receptor function was also observed in electrophysiological studies. Thus in sodium glutamate containing buffer the potency of DbATP (pEC50=5.55) was approximately 22-fold higher than in NaCl containing buffer (pEC50=4.20). This study has demonstrated that P2X7 receptor function can be markedly affected by a wide range of ions and that physiological concentrations of sodium and chloride ions, as well as divalent cations, contribute to the low potency of ATP as an agonist at this receptor.
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  • 10
    ISSN: 1432-1912
    Keywords: Key words ATP receptors ; Structure ; Function ; Transduction ; Recombinant receptors ; Cation channels ; Electrophysiology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Significant advances in understanding of P2X purinoceptor pharmacology have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated. Fortunately, inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleotide breakdown. Despite these issues, convincing evidence for P2X receptor heterogeneity, from data with agonists, has recently been reported. A number of new antagonists at P2X purinoceptors have also recently been described which to some degree appear to be more specific and useful than earlier antagonists like suramin. It is now apparent that suramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which it blocks the P2X purinoceptor. Advances in the use of radiolabelled nucleotides as radioligands for binding studies has allowed the demonstration of P2X purinoceptors in a variety of tissues throughout the body including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P2X purinoceptor genes have been cloned but operational studies suggest that more than two types exist. The cloning studies have also demonstrated a unique structure for the P2X purinoceptor which differentiates it from all other ligand-gated ion channel receptors. Further studies on P2X purinoceptor operation and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide receptors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activation of P2X purinoceptors. This will require the identification of better drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents.
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